Interpretive Summary: Fumonisins are toxins made by molds that grow on corn. Fumonisins cause disease in animals and are suspected of causing cancer in humans. A series of investigations was done to determine if fumonisins cause tumors in animals and to study how fumonisins cause apoptosis, a specialized process for causing cell death. Fumonisin B1 (FB1), the most common type of fumonisin, was fed to rats and mice for 2 years. It caused kidney tumors in male rats and liver tumors in female mice. In additional studies in rats and mice, FB1 blocked an enzyme called ceramide synthase that is important for making sphingolipids, a type of fat that is important for regulating cell function. The degree of enzyme blockage observed was related to amount of apoptosis seen in the animals' tissues. We also found that a molecule called tumor necrosis factor alpha is also involved in the apoptotic responses to FB1 and may work together with sphingolipids to govern apoptosis. Determining that fumonisins causes tumors in animals and learning how they induce apoptosis, believed to have an important role in tumor development, are important steps in assessing the extent to which fumonisins may affect human health.

Technical Abstract:
Fumonisins are fungal metabolites of Fusarium moniliforme (=F. Verticillioides) that are found on corn and in corn-based foods. They are suspected human esophageal carcinogens. They inhibit ceramide synthase in vitro, enhance tumor necrosis factors alpha (TNFalpha) production, and cause apoptosis. Fumonisin B1 (FB1) was fed to rats and mice for 2 years or, in separate studies, given to rats or mice for up to 4 weeks. Kidney tubule adenomas and carcinomas were found in male rats fed >50 ppm, whereas liver adenomas and carcincomas were found in female mice fed >50 ppm for 2 years. In the short-term studies, increases in tissue concentrations of the ceramide synthase substrates sphinganine (Sa) and sphingosine (So) were increased and the increases in Sa and in the ratio Sa/SO were correlated with apoptosis. Furthermore, apoptosis and SA effects were ameliorated in the liver of mice lacking either the TNFR1 or the TNFR2 tumor necrosis factor alpha (TNFalpha) receptors. These studies show that FB1 is carcinogenic to rodents. Furthermore, the findings of these studies support the hypothesis that sphingolipids, TNFalpha, and apoptosis play important roles in fumonisin toxicity and carcinogenicity.